The invention relates to the synthesis of D- and AL- xcex1-amino acids and D- and L- xcex1-amino aldehydes from olefins and other unsaturated substrates. More particularly, the invention relates to a two step synthesis in which the first step is an asymmetric xcex2-aminohydroxylation of the olefin or unsaturated substrate and the second step is an oxidation of the deprotected product of the first step to form a D- or L- xcex1-amino acid or a D- or L- xcex1-amino aldehyde.
D- and L- xcex1-amino acids are key building blocks for peptides, proteins, pharmaceuticals, and other important biomolecules. Naturally occurring L- xcex1-amino acids are readily available from biological sources. However, enantiomerically pure D- xcex1-amino acids and unnatural L- xcex1-amino acids are more difficult to obtain. Due to their chirality, these compounds can be difficult to synthesize in an enantiomerically pure form. Several compounds within this class have significant economic value. Similarly, and D- and L- xcex1-amino aldehydes are a re-occurring motif in biologically and pharmaceutically important molecules but are difficult to obtain in enantiomerically pure form.
Over the past 20 years, separate and distinct synthetic methodologies have been developed by Sharpless et al. for the vicinal hydroxyamination of olefins. There are three major groups of oxyamination procedures which produce aminoalcohols (Sharpless et al. J. Am. Chem. Soc. 1975, 97, 2305; Sharpless et al. J. Org. Chem. 1978, 43, 2628; Sharpless et al. J. Org. Chem. 1980, 45, 2257), hydroxysulfonamides (Sharpless et al. J. Org. Chem. 1976, 41, 177; Sharpless et al. J. Org. Chem. 1978, 43, 2544; Sharpless et al. J. Org. Chem. 1979, 44, 1953; Sharpless et al. Org. Syn. 1980, 61, 85) or hydroxycarbamates (Sharpless et al. J. Am. Chem. Soc. 1978, 100, 3596; Sharpless et al. J. Org. Chem. 1980, 45, 2710; Sharpless et al. U.S. Pat. No.""s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729). Each oxyamination procedure has unique reaction conditions and includes variations in solvents, auxiliary salts, nucleophiles, temperature, stoichiometric v. catalytic amounts of osmium species and stoichiometric v. catalytic amounts of ligand. Each procedure is highly dependant on the nature of the substrate and possesses unique properties which afford different yields, chemoselectivities, stereoselectivities, regioselectivities and enantioselectivitive outcomes.
1. Aminoalcohols
The first reported oxyamination procedure (Sharpless et al. J. Am. Chem. Soc. 1975, 97, 2305) generated aminoalcohols from mono and di substituted olefins, using stoichiometric quantities of a tri-oxo(tert-butylimido)osmium species. The procedure required reductive cleavage of the osmate ester which was performed with lithium aluminum hydride and afforded tertiary vicinal aminoalcohols. Yields were good to excellent, but in some cases, the side product vicinal diol was formed as an undesired by-product. The stereochemistry of addition, in methylene chloride or pyridine, was exclusively cis (Sharpless et al. J. Org. Chem. 1978, 43, 2628). In addition, the carbon-nitrogen bond formed was, in every case, at the least substituted olefinic carbon atom. Di and tri-substituted olefins reacted much slower with the generated imido reagent than with monosubstituted alkenes; tetrasubstituted alkenes yielded only the corresponding diol. However, by using a coordinating solvent such as pyridine, higher yields and higher ratios of aminoalcohol to diol were reported. Sharpless et al. J. Org. Chem. 1980, 45, 2257; Sharpless et al. J. Org. Chem. 1976, 41, 177; Sharpless et al. J. Org. Chem. 1978, 43, 2544.
2. Hydroxysulfonamides
Sharpless et al. first demonstrated that hydroxysulfonamides could be obtained using either stoichiometric or catalytic amounts of 1% osmium tetraoxide in the presence of 1.5-5 equivalents of Chloramine-T trihydrate (TsSO2NClNa.3H2O, Ts=tosylate; commercially obtained) to effect cis addition of a hydroxyl (OH) and an arylsulfonamide moiety (Arxe2x80x94SO2NH) across a mono or disubstituted olefinic linkages (Sharpless et. al. J. Org. Chemistry 1976, 41, 177).
Two procedures were developed to effect hydroxyamination of olefins using sulfonamides. (Sharpless et al. Org. Syn. 1980, 61, 85). The first procedure used phase transfer catalysis conditions at 55-60xc2x0 C. With 1% OsO4, 1:1 v/v, 0.20 Molar CHCl3/H2O, and benzyltriethylammonium chloride as the phase transfer catalyst. The chloramine T-trihydrate (TsSO2NClNa.3H2O) was either added directly or formed in situ in water; this solution was then directly used in the phase transfer mixture. The in situ procedure, for generating the chloramine salts, involved stirring a suspension of the arylsulfonamide with an equivalent of sodium hypochlorite (Clorox) until a homogenous solution was obtained. The yields were comparable with those obtained with isolated chloramine salts and the procedure was found most effective for monosubstituted and 1,2 disubstituted olefins. The phase transfer method, however, gave poor results with trisubstituted and 1,1-disubstituted olefins and the procedure did not succeed with diethyl fumarate and 2-cyclohexen-1-one. Sharpless et al. J. Org. Chem. 1978, 43, 2544.
A second procedure was carried out in tert-butyl alcohol at 55-60xc2x0 C. with 1% OsO4, silver nitrate (with or without) and commercially obtained chloramine T-trihydrate (TsSO2NClNa.3H2O) which provided the only source (of water. The procedure did not succeed with tetramethylethylene and cholesterol, and negative results were found with most hindered tri- and tetrasuostituted olefins. Sharpless et. al. J. Org. Chemistry 1976, 41, 177; Sharpless et al. Org. Syn. 1980, 61, 85. The addition of divalent metal salts such as AgNO3 and Hg(NO3)2 improved some reactions, however, other reactions suffered deleterious effects from the addition of the metal salts. Sharpless et al. J. Org Chem. 1978, 43, 2544; Sharpless et. al. J. Org. Chemistry 1976, 41, 177.
Further elaboration on either procedure showed that other sulfonamide derivatives (ArSO2NClNa) could be successfully employed in addition to chloramine T, where Ar=phenyl, o-tolyl, p-chlorophenyl, p-nitrophenyl, and o-carboalkoxyphenyl. Sharpless et al. J. Org. Chem.1978, 43, 2546.
Neither the phase transfer catalyst or tert-butyl alcohol procedures succeeded with tetramethyl ethylene, 2,3-dimethyl-2-octene, diethyl fumarate, or 2-cyclohexen-1-one. Negative results were also obtained with most hindered tri- and tetrasubstituted olefins. Herranz E., MIT Ph.D. Thesis, 1979, 33.
Solvent conditions for the synthesis of the hydroxysulfonamides included organic solvents such as acetonitrile, tert-butyl alcohol, isopropyl alcohol and chloroform which was in contact with the aqueous phase in the phase transfer catalyst procedure.
The tert-butyl alcohol procedure (including other solvents used) was not run with added water; the phase transfer catalyst (PTC) procedure required a biphasic mixture of 1:1 v/v chloroform/water. Recently, however, an improvement was reported which used a 1:1 ratio of organic solvent to water in a homogeneous, rather than a biphasic solution or organic solvent with small amounts of water. These conditions were found to provide optimum enantioselectivity, regioselectivity and improved yields from either the previously described t-butyl alcohol or PTC conditions. Sharpless et al. Angew. Chemie Intl Ed. 1996, 35, 451.
The use of chiral ligands with sulfonamides provides enantioselectivity and has been observed to both accelerate and decelerate the rate of catalysis. The hydroxysulfonamide process is a stereoselective cis process. The presence of ligands also has a dramatic effect on the regioselectivity. In a study with no ligand present with methyl cinnamate, the two regioisomers were present in a 2:1 ratio. With the addition of ligand, the ratio was improved to 5:1 or greater. Another positive effect of the ligand was its ability to suppress formation of diol by-product. Agew. Chemie Intl Ed. 1996, 35, 451.
Peferred ligands for use with sulfonamides have included the use of monovalent cinchona alkaloids or the bivalent phthalazine based, commercially available (DHQ)2PHAL and (DHQD)2PHAL alkaloids. Sharpless et al. Angew. Chemie Intl Ed. 1996, 35, 451.
Temperature conditions for the hydroxysulfonamide asymmetric aminohydroxylations have varied from 60xc2x0 C. to 25xc2x0 C. for reactions including sulfonamides, auxiliary salts, ligands, phase transfer catalysts and stoichiometric or catalytic osmium species, primarily in organic solvents with small amounts of water. Recently, it has been shown that temperature can been lowered to 0xc2x0 C. while running the reaction, to obtain product by filtration; many hydroxysulfonamides tend to be highly crystalline Sharpless et al. Acta Chemica Scandinavica 1996 in press.
Cleavage of the sulfonamides, to free aminoalcohols, have been accomplished via standard deprotection conditions including dissolving metals (Na, NH3; Sharpless et al J. Org. Chem 1976, 41, 177) and HBr, acetic acid and phenol (Fukuyama et al. Tetrahedron Lett. in press)
3. Hydroxycarbamates
A drawback with the hydroxysulfonamide procedure was that cleavage conditions were too strong for some substrates. The use of carbamates to protect the nitrogen, however, provided a methodology which avoided the use of harsh acids or reducing deprotection problems found with hydroxysulfonamides (Sharpless et al. J. Am. Chem. Soc. 1978, 100, 3596; Sharpless et al. J. Org. Chem. 1980, 45, 2710; Sharpless et al. Org. Syn. 1981, 61, 93; Sharpless et al. U.S. Pat. No.""s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729).
Sharpless first demonstrated the synthesis of hydroxycarbamates with the use of N-chloro-N-argentocarbamates (Sharpless et al J. Am. Chem. Soc. 1978 100, 3596). The N-chloro-N-argentocarbamates were generated in situ via the addition of N-chlorosodiocarbamates and silver nitrate to a solution of the olefin in acetonitrile or tert-butanol with trace amounts of water (4.5 molar equivalents based on olefin) and 1% of osmium tetroxide catalyst to generate vicinal hydroxycarbamates in generally good yields. The methodology was reported to be more effective with electron deficient olefins such as dimethyl fumarate and trisubstituted olefins were reported to be less readily oxyaminated with N-chloro-N-argentocarbamates than with the chloramine-T procedures (Sharpless et. al. J. Org. Chem. 1976, 41, 177).
Sodio-N-chlorocarbamates were always first converted to either argento or mercurio salt analogs. The addition of the AgNO3 or Hg(NO3)2 salts, to make N-chloro-N-argentocarbamates or mercuric salt analogs, was crucial for the reaction to retain its desired properties. (Sharpless et al J. Org. Chem., 1980, 45, 2711). This was in contrast to the sulfonamide conditions, where the sodio-N-chloro-sulfonamide salts could be used directly with either the ti-butanol or chloroform/waterxe2x80x94phase transfer catalyst procedures (Sharpness et al. J. Org. Chem. 1978, 43, 2544).
The addition of nucleophiles such as tetraethylammonium acetate were also proven to be beneficial to the reaction in the procedures using the silver and mercury salts of the chloramines from carbonates. Alternatively, the reactivity and yields were enhanced by addition of excess AgNO3 and Hg(NO3)2 (over that needed to react with the NaClNCOOR salt) Sharpless et al. J. Org Chem. 1980, 45, 2710.
Preferred conditions included employment of ROCONClNa+Hg(NO3)2+Et4NOAc with N-chloro-N-sodiocarbamates; these conditions were recommended as the best procedure for mono, di and tri substituted olefins even including some olefins unreactive in all of the various chloramine T based processes. (Sharpless et al. Org. Syn. 1981, 61, 93).
Among the carbamates tried, it was found that both benzyl N-chloro-N-argentocarbamate and tert-butyl N-chloro-N-argentocarbamates (or mercurio analogs) were among the most effective oxidants, especially with addition of nucleophiles such as tetraethylammonium acetates Other carbamates such as isopropyl, ethyl, menthyl and bornyl derivatives were also used, however, chemo, regio and stereoselectivities were lower. Virtualy no asymmetric induction was observed when chiral menthyl or bornyl derived carbamates were employed for hydroxyaminations. (Sharpless et al J. Am. Chem. Soc. 1978 100, 3596).
Sharpless disclosed the use of stoiciometric amounts of a first generation monovalent alkaloid ligand with a tert-butyl derived N-chloro-N-argent(carbamate for hydroxyamination in a series of patent applications directed to ligand accelerated catalytic asymmetric dihydroxylation. These disclosures illustrated an hydroxyamination on trans-stilbene with the use of 1.0 equivalent (stoichiometric to olefin) of monovalent DHQD-p-chlorobenzoate (DHQD=hydroquinidine) ligand, 1 mol % osmium tetroxide, silver nitrate (figure) or mercuric chloride (0.80 equivalents; in protocal), 0.09 Molar acetonitrile (93.11 volume % acetonitrile)/water mix (6.89 volume % water) and tertbutyl derived N-chloro-N-argeniocarbamate (1.45 equivalents) at 20xc2x0 C. (figure) or 60xc2x0 C. (protocal) for 1 hour. The disclosure reported a 51% ee with a 93% yield of aminoalcohol. (Sharpless et al. U.S. Pat. No.""s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729).
In a review on ligand accelerated catalysis, Sharpless et al. noted that a 92% ee had been achieved in a stoichiometric reaction of trioxo-(tert-butylimido) osmium with stilbene in the presence of DHQD-CLB at ambient temperatures (Sharpless et al. Angew. Chem. Int. Ed. Engl. 1995, 34, 1059, ref. 80 xe2x80x9cunpublished resultsxe2x80x9d); this mention did not disclose reaction conditions.
Recently, an oxyamination reaction for the hemisynhesis of taxol and analogs was reported using a tertbutyl derived N-chloro-N-argentocarbamate, excess silver nitrate or other metallic salts, with the use of either catalytic or stoichiometric amounts of osmium and the addition of stoichiometric amounts of monovalent DHQD (hydroquinidine), DHQ (hydroquinine) ligands in an unsuccessful attempt to influence the diastereoselectivity and the regioselectivity of the aminohydroxylation process. Solvent conditions varied from acetonitrile, toluene or pyridine, and the reactions were carried out at 4xc2x0 C. to room temperature, in the dark. The study reported that quinuclidine ligand. had no effect on the amino alcohol yields but found that the addition of chiral tertiary amines had some beneficial effect on the yields of the various amino alcohol isomers formed. (Mangatal et al. Tetrahedron 1989 45, 4177). However, the two pseudoenantiomeric alkaloid ligands (i.e. DHQ-OAc and DHQD-OAc; OAc=acetate) gave a mixture of stereo and regionsomeric products. The result indicates that this particular hydroxyamination process (be it stoichiometric or catalytic was unclear) had exhibited no xe2x80x9casymmetricxe2x80x9d effects. The procedure can therefore not be regarded as an asymmetric aminohydroxylation.
As a whole, the prior art uses hydroxycarbamates which always run at room temperature with either argento or mercurio salt analogs, monovalent ligands, stoichiometric or catalytic osmium species and organic solvents with trace amounts of water. (Sharpless et al. J. Am. Chem. Soc. 1978, 100, 3596; Sharpless et al. J. Org. Chem. 1980, 45, 2710; Sharpless et al. U.S. Pat. No.""s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729).
Cleavages of the hydroxycarbamates, to free aminoalcohols, are well known in the art and include mild acid or base hydrolysis and catalytic hydrogenolysis, depending on the attached functionality to the carbamate. (Greene, Protective Groups in Organic Synthesis, 1981, Wiley, 1st edn. pp. 223-249).
What is needed is an improved method for synthesizing D- and L- xcex1-amino acids and D- and L- xcex1-amino aldehydes using olefins as starting materials.
One aspect of the invention is directed to methods for the conversion of olefinic substrates to form asymmetric xcex1-amino acid products. The method employs two steps.
In the first step the olefinic substrate is catalytically converted by means of an addition reaction to form a protected asymmetric xcex2-aminohydroxide product having a protected amino radical and a hydroxyl radical. The conversion employs a reaction solution which includes a source of the protected amino radical, osmium as a catalyst, a chiral ligand or enantiomerically directing the asymmetric addition, and a solvent.
There are several modes for accomplishing this first step. In a first preferred mode, the source of the protected amino radical is a carbamate. In a second preferred mode, the source of the protected amino radical is a sulfonamide. In the first preferred mode, the chiral ligand may be present and soluble within the reaction solution at a concentration within a range approximately excellent to the catalytic concentration of the osmium. The solvent may have an organic component within which the olefinic substrate and carbamate are present and soluble at stoichiometric concentrations and within which the osmium is present and soluble in catalytic concentrations. The solvent may also include an aqueous component present at 10% or greater on a volume basis. Alternatively, the chiral ligand may be present and soluble within the reaction solution at a molar concentration which is approximately equivalent to the catalytic concentration of the osmium but which is less than the stoichiometric concentration of the olefinic substrate and carbamate.
In the second step, the hydroxyl radical on the asymmetric xcex2-aminohydroxide product of the first step is oxidized to form the asymmetric xcex1-amino acid product. The protected amino radical may be deprotected either prior to or after the oxidation of the hydroxyl radical.
Another aspect of the invention is directed to methods for the conversion of olefinic substrates to form asymmetric xcex1-amino aldehyde products. This second aspect of the invention employs two steps, viz.
1. An addition reaction wherein the olefinic substrate is converted to the protected asymmetric xcex2-aminohydroxide product described above; and
2. An oxidation step where the product of the first step is converted to an asymmetric xcex1-amino aldehyde product.
The protected amino radical may be deprotected either before or after the oxidation step. In a preferred mode, the deprotection is perform simultaneously with the oxidation step.